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J. Biol. Chem., Vol. 281, Issue 36, 26540-26551, September 8, 2006

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Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor , and the Coactivator Peroxisome Proliferator-activated Receptor Coactivator-1^*

Xunshan Ding, Kristin Lichti, Insook Kim, Frank J. Gonzalez, and Jeff L. Staudinger¹

From the Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045 and the Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

Animal studies reveal that fasting and caloric restriction produce increased activity of specific metabolic pathways involved in resistance to weight loss in liver. Evidence suggests that this phenomenon may in part occur through the action of the constitutive androstane receptor (CAR, NR1I3). Currently, the precise molecular mechanisms that activate CAR during fasting are unknown. We show that fasting coordinately induces expression of genes encoding peroxisome proliferator-activated receptor coactivator-1 (PGC-1), CAR, cytochrome P-450 2b10 (Cyp2b10), UDP-glucuronosyltransferase 1a1 (Ugt1a1), sulfotransferase 2a1 (Sult2a1), and organic anion-transporting polypeptide 2 (Oatp2) in liver in mice. Treatments that elevate intracellular cAMP levels also produce increased expression of these genes in cultured hepatocytes. Our data show that PGC-1 interaction with hepatocyte nuclear factor 4 (HNF4, NR2A1) directly regulates CAR gene expression through a novel and evolutionarily conserved HNF4-response element (HNF4-RE) located in its proximal promoter. Expression of PGC-1 in cells increases CAR expression and ligand-independent CAR activity. Genetic studies reveal that hepatic expression of HNF4 is required to produce fasting-inducible CAR expression and activity. Taken together, our data show that fasting produces increased expression of genes encoding key metabolic enzymes and an uptake transporter protein through a network of interactions involving cAMP, PGC-1, HNF4, CAR, and CAR target genes in liver. Given the recent finding that mice lacking CAR exhibit a profound decrease in resistance to weight loss during extended periods of caloric restriction, our findings have important implications in the development of drugs for the treatment of obesity and related diseases.

Received for publication, January 31, 2006 , and in revised form, June 28, 2006.

^* This work was supported by National Institutes of Health Grants RR17708 and R01DK068443. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Dr., 5044 Malott Hall, Lawrence, KS 66045. Tel.: 785-864-3951; Fax: 785-864-5219; E-mail: stauding{at}ku.edu.

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